Bridged n-bicyclic sulfonamido inhibitors of gamma secretase   

This application claims priority from U.S. Provisional application No. 60/709,961, filed Aug. 19, 2005, which is incorporated by reference, in its entirety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) to provisional application U.S. Ser. No. 60/709,961 filed Aug. 19, 2005 which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to bridged N-bicyclic sulfonamido compounds, which inhibit gamma secretase and β-amyloid peptide release and/or its synthesis. Therefore, the N-bicyclic sulfonamido compounds are useful in the prevention of cognitive disorders in patients susceptible to cognitive disorders and/or in the treatment of patients with cognitive disorders in order to inhibit further deterioration in their condition.

2. State of the Art

Alzheimer\'s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.

The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down\'s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.

The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the β-amyloid peptide (βAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner et al., Biochem. Biophys. Res. Commun., 120:885-890 (1984) The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Molecular biological and protein chemical analyses have shown that the β-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the formula of the gene encoding APP has demonstrated that β-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). Sequential, processing of the precursor protein by the enzymes referred to generically as beta- and gamma-secretases, give rise to the β-amyloid peptide fragment. Both enzymes have now been molecularly cloned, and characterized to differing levels.

Several lines of evidence indicate that progressive cerebral deposition of β-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, Neuron, 6:487-498 (1991). The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate et al., Nature, 349:704-706 (1990); Chartier Harlan et al., Nature, 353:844-846 (1989); and Murrell et al., Science, 254:97-99 (1991.) Another such mutation, known as the Swedish variant, is comprised of a double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform was found in a Swedish family) was reported in 1992 (Mullan et al., Nature Genet., 1:345-347 (1992). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the β-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP metabolism, and subsequent deposition of it β-amyloid peptide fragment, can cause AD.

Despite the progress which has been made in understanding the underlying mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting β-amyloid peptide release and/or its synthesis in vivo.

One approach toward inhibiting amyloid peptide synthesis in vivo is by inhibiting gamma secretase, the enzyme responsible for the carboxy-terminal cleavage resulting in production of β-amyloid peptide fragments of 40 or 42 residues in length. The immediate substrates for gamma secretase are β-cleaved, as well as α-cleaved carboxy-terminal fragments (CTF) of APP. The gamma-secretase cleavage site on β- and α-CTF fragments occurs in the predicted transmembrane domain of APP. Inhibitors of gamma-secretase have been demonstrated to effect amyloid pathology in transgenic mouse models (Dovey, H. F., V. John, J. P. Anderson, L. Z. Chen, P. de Saint Andrieu, L. Y. Fang, S. B. Freedman, B. Folmer, E. Goldbach, E. J. Holsztynska et al. (2001). “Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.” J. Neurochem 76(1): 173-81.)

Gamma secretase is recognized to be a multi-subunit complex comprised of the presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen 2 (De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12; Edbauer, D., E. Winkler, J. T. Regula, B. Pesold, H. Steiner and C. Haass (2003). “Reconstitution of gamma-secretase activity.” Nat Cell Biol 5(5): 486-8; Kimberly, W. T., M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe and D. J. Selkoe (2003). “Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.” Proc Natl Acad Sci USA 100(11): 6382-7). Much evidence indicates that PS comprises the catalytic moiety of the complex, while the other identified subunits are necessary for proper maturation and sub-cellular localization of the active enzyme complex (reviewed in De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12.) Consistent with this hypothesis: PS knock-out mice exhibit significant reductions in β-amyloid production (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura and F. Van Leuven (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Haass, C. and D. J. Selkoe (1998). “Alzheimer\'s disease. A technical KO of amyloid-beta peptide.” Nature 391(6665): 339-40; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2); point mutations of putative active site aspartate residues in PS trans-membrane domains inhibit β-amyloid production in cells in a dominant negative fashion (Wolfe, M. S., W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T. Kimberly and D. J. Selkoe (1999). “Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.” Nature 398(6727): 513-7; Kimberly, W. T., W. Xia, T. Rahmati, M. S. Wolfe and D. J. Selkoe (2000). “The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation.” J Biol Chem 275(5): 3173-8); active site directed substrate-based transition state isosteres designed to inhibit gamma secretase directly conjugate to PS (Esler, W. P., W. T. Kimberly, B. L. Ostaszewski, T. S. Diehl, C. L. Moore, J. Y. Tsai, T. Rahmati, W. Xia, D. J. Selkoe and M. S. Wolfe (2000). “Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-i.” Nat Cell Biol 2(7): 428-34; Li, Y. M., M. Xu, M. T. Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C. Lellis, A. Nadin, J. G. Neduvelil et al. (2000). “Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.” Nature 405(6787): 689-94); finally, allosteric gamma secretase inhibitors have likewise been demonstrated to bind directly to PS (Seiffert, D., J. D. Bradley, C. M. Rominger, D. H. Rominger, F. Yang, J. E. Meredith, Jr., Q. Wang, A. H. Roach, L. A. Thompson, S. M. Spitz et al. (2000). “Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.” J Biol Chem 275(44): 34086-91.)

Current evidence indicates that in addition to APP processing leading to β-amyloid synthesis, gamma-secretase also mediates the intra-membrane cleavage of other type I transmembrane proteins (reviewed in Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84, see also Struhl, G. and A. Adachi (2000). “Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.” Mol Cell 6(3): 625-36.) Noteworthy among the known substrates of gamma-secretase is mammalian Notch 1. The Notch 1 protein is important for cell fate determination during development, and tissue homeostasis in the adult. Upon ligand engagement via the Notch ecto-domain, Notch undergoes sequential extra-cellular and intra-membrane processing analogous to APP. The intra-membrane processing of Notch mediated by gamma secretase leads to release of the Notch intracellular domain (NICD). The NICD fragment mediates Notch signaling via translocation to the nucleus, where it regulates expression of genes mediating cellular differentiation in many tissues during development, as well as in the adult.

Disruption of Notch signaling via genetic knock-out (KO) results in embryonic lethal phenotype in mice (Swiatek, P. J., C. E. Lindsell, F. F. del Amo, G. Weinmaster and T. Gridley (1994). “Notch1 is essential for postimplantation development in mice.” Genes Dev 8(6): 707-19; Conlon, R. A., A. G. Reaume and J. Rossant (1995). “Notch1 is required for the coordinate segmentation of somites.” Development 121(5): 1533-45.) The Notch KO phenotype is very similar to the phenotype observed PS1 KO mice, and precisely reproduced by PS1/PS2 double KO mice (De Strooper et al. (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Donoviel, D. B., A. K. Hadjantonakis, M. Ikeda, H. Zheng, P. S. Hyslop and A. Bernstein (1999). “Mice lacking both presenilin genes exhibit early embryonic patterning defects.” Genes Dev 13(21): 2801-10; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2.) This convergence of phenotypes observed in knock-out mice of either the substrate (Notch) or the enzyme (PS) suggests that inhibitors of gamma secretase that also inhibit Notch function may be limited as therapeutic agents owing to the importance of Notch function in adult tissues (Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84.) As APP knock-out mice develop normally and without an overt phenotype Zheng, H., M. Jiang, M. E. Trumbauer, R. Hopkins, D. J. Sirinathsinghji, K. A. Stevens, M. W. Conner, H. H. Slunt, S. S. Sisodia, H. Y. Chen et al. (1996). “Mice deficient for the amyloid precursor protein gene.” Ann N Y Aced Sci 777: 421-6; Zheng, H., M. Jiang, M. E. Trumbauer, D. J. Sirinathsinghji, R. Hopkins, D. W. Smith, R. P. Heavens, G. R. Dawson, S. Boyce, M. W. Conner et al. (1995). “beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.” Cell 81(4): 525-31, the cumulative evidence, therefore, suggests that preferred gamma secretase inhibitors would have selectivity for inhibiting gamma secretase processing of APP over gamma secretase processing of Notch.

SUMMARY

In a broad aspect, the invention provides compounds of Formula I:

including stereoisomers, tautomers, mixtures of stereoisomers and/or tautomers, or pharmaceutically acceptable salts thereof

wherein

the A-ring is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, where each ring is optionally substituted at a substitutable position with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, C0-C3alkylCO2R′, heteroaryl, heterocycloalkyl, aryl, aralkyl, or —SO2NR10R11;

R1 and R2 combine to form a [3.3.1] or a [3.2.1] ring system, where the nitrogen is attached to the two bridgehead carbons, where 0 or 1 of the carbons in the ring system is optionally replaced with an —O—, —S(O)x—, or —NR15— group; where x is 0, 1 or 2; and where the [3.3.1] or [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O—(C1-C4 alkyl)-O—, —S—(C1-C4 alkyl)-S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR′, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with an aryl, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is hydrogen, C1-C6 alkyl or —SO2-aryl, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with aryl, hydroxyl, or halogen, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R15 is hydrogen, aryl, heteroaryl, —SO2R′, —C(O)R′, —C(O)OR′, or C1-C6 alkyl optionally substituted with aryl, hydroxyl, or halogen, where the aryl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11.

The compounds of Formula I inhibit β-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of Alzheimer\'s Disease (AD) in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The invention also, encompasses pharmaceutical compositions containing the compounds of Formula I, and methods employing such compounds or compositions in the treatment of cognitive diseases, including Alzheimer\'s disease.

The invention also provides a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer\'s disease, for helping prevent or delay the onset of Alzheimer\'s disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer\'s disease in those who would progress from MCI to AD, for treating Down\'s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson\'s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration or diffuse Lewy body type of Alzheimer\'s disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of Formula I.

In another aspect, the invention provides methods of preparing the compounds of interest, as well as intermediates useful in preparing the compounds of interest.

DETAILED DESCRIPTION

As described above, the invention provides for compounds according to Formula I.

In one aspect, the A-ring is phenyl, C3-C8 cycloalkyl, heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, or heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where each of the above rings is optionally substituted at a substitutable position with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, C0-C3alkylCO2R′, heteroaryl, heterocycloalkyl, aryl, aralkyl, or —SO2NR10R11.

In another aspect, the invention provides a compound of Formula II, i.e., a compound of Formula I with the formula:

where 0 or 1 of the carbons in the [3.2.1] ring system is optionally replaced with an —O—, —S(O)x—, or —NR15— group;

x is 0, 1 or 2

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O—(C1-C4 alkyl)-O—, —S—(C1-C4 alkyl)-S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with an aryl, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with aryl, hydroxyl, or halogen, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy; haloalkyl, haloalkoxy, CN or NO2;

R15 is hydrogen, aryl, heteroaryl, —SO2R′, —C(O)R′, —C(O)OR′, or C1-C6 alkyl optionally substituted with aryl, hydroxyl, or halogen, where the aryl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11.

In still another aspect, the invention provides compounds of Formula III, i.e. compounds of Formula II having the formula:

wherein

the A-ring is aryl (such as phenyl or naphthyl, preferably phenyl), which is optionally substituted at a substitutable position with halogen C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, C0-C3alkylCO2R′, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl, or —SO2NR10R11;

wherein 0 or 1 of the carbons in the [3.2.1] ring system is optionally replaced with an —O—, —S(O)x—, or —NR15— group; and where the [3.2.1] ring is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O—(C1-C4 alkyl)-O—, —S—(C1-C4 alkyl)-S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In still another aspect, the invention provides compounds of Formula IIIa, i.e., compounds of the Formula III having the following formula:

wherein,

0 of the carbons in the [3.2.1] ring system are optionally replaced with an —O—, —S(O)X, or —NR15— group;

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O—(C1-C4 alkyl)-O—, —S—(C1-C4 alkyl)-S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13;

R3, R4, R5, R6, R7 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, hydroxyl, C1-C6 alkoxy, C1-C3 alkyl-OH, —C1-C3 alkyl-alkoxy, phenyloxy, —S(O2)R′, —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a heterocycloalkyl or a heteroaryl ring which is optionally substituted with 1, 2, 3, or 4 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with an phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl (such as CF3), haloalkoxy (such as OCF3), hydroxyl, CN, phenyloxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11.

In another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with oxo, —O(C1-C2 alkyl)O—, or —S(C1-C2 alkyl)S—.

In another aspect the invention provides compounds of Formula III or IIIa wherein the [3.2.1] ring is substituted with —O—SO2—(C1-C6 alkyl).

In still another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with ═N—NR12, or ═N—O—R13; where

R12 is hydrogen, C1-C6 alkyl or —SO2— phenyl, where the phenyl is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2; and

R13 is hydrogen or C1-C6 optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In yet another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with ═N—NR12, where R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 4 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2.

In yet still another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with ═N—O—R13; where R13 is hydrogen.

In yet still another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is ═N—O—R13; where R13 is C1-C6 optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2.

In yet still another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is not substituted.

In yet another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with aryl or heteroaryl, such as phenyl or pyridyl, both aryl and heteroaryl are optionally substituted with halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In yet still another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is C2-C6 alkenyl.

In yet another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is hydroxyl or C1-C6 alkoxy.

In yet still another aspect, the invention provides compounds of Formula III, wherein, 1 of the carbons in the [3.2.1] ring system is optionally replaced with an —O—, —S(O)x—, or —NR15— group, where R15 is hydrogen, C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, or phenyl, where the phenyl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2, and where x is 0, 1 or 2.

In another aspect, the invention provides compounds of Formula IIIb, i.e., compounds of Formula III having the following formula:

wherein

R3, R4, R5, R6, R7 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, hydroxyl, C1-C6 alkoxy, —C1-C3 alkyl-OH, —C1-C3 alkyl-alkoxy, phenoxy, —S(O2)R′, —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a heterocycloalkyl or a heteroaryl ring which is optionally substituted with 1, 2, 3, or 4 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R15 is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO2R′, —C(O)R′, —C(O)OR′, or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl (such as CF3), C1-C4 haloalkoxy (such as OCF3), amino, NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C4 alkyl), CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy, —SO2—(C1-C6 alkyl), C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11.

In yet another aspect, the invention provides compounds of Formula IIIb, wherein R15 is hydrogen.

In still another aspect, the invention provides compounds of Formula IIIb, wherein R15 is C1-C6 alkyl.

In yet still another aspect, the invention provides compounds of Formula IIIb, wherein R15 is C1-C6 alkyl substituted with phenyl, hydroxyl, or halogen, where the phenyl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In still yet another aspect, the invention provides compounds of Formula IIIb, wherein R15 is phenyl optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In another aspect, the invention provides compounds of Formula III or IIIa, wherein the [3.2.1] ring is substituted with oxo, —O(C1-C2 alkyl)O—, or —S(C1-C2 alkyl)S—.

In another aspect, the invention provides compounds of Formula IIIc, i.e., compounds of Formula III having the following formula:

wherein

R3, R4, R5, R6, R7 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, hydroxyl, C1-C6 alkoxy, —C1-C3alkyl-OH, —C1-C3 alkyl-alkoxy, phenoxy, —S(O2)R′, —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a heterocycloalkyl or a heteroaryl ring which is optionally substituted with 1, 2, 3, or 4 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11,

In another aspect, the invention provides compounds of Formula IIId, i.e., compounds of Formula III having the following formula:

wherein

R3, R4, R5, R6, R7 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, ON, hydroxyl, C1-C6 alkoxy, —C1-C3 alkyl-OH, —C1-C3 alkyl-alkoxy, phenoxy, —S(O2)R′, —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a heterocycloalkyl or a heteroaryl ring which is optionally substituted with 1, 2, 3, or 4 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; or

R4 and R5, or R5 and R6 and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R10 and R11 at each occurrence are independently hydrogen or C1-C6 alkyl, where the alkyl is optionally substituted with phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; or

R10 and R11 together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R12 is C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2;

R13 is hydrogen or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO2; and

R′ and R″ are independently hydrogen, C1-C6 alkyl, haloalkyl, C2-C6 alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C1-C6 alkyl, —C(O)OR′, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, pyridyl, phenyl, NO2, or —SO2NR10R11.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein, R3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, haloalkyl, or CN;

R4 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloalkoxy, CN, phenyloxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R5 is hydrogen, C1-C6 alkyl, —SO2—NR10R11, or halogen.

In still other aspects, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein, R4 is hydrogen, halogen (in one aspect, I, Br, F or Cl), C1-C6 alkyl optionally substituted with halogen or hydroxyl, C1-C6 alkoxy, OCF3, or CN.

In yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is phenyloxy, —SO2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl.

In still another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is —NR10R11.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is —NR10R11, and R3, R5, R6, and R7 are H.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3, R4, R5, R6, and R7 are independently hydrogen, halo, CF3, CHF2 or methyl.

In yet still another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3, R5, R6, and R7 are hydrogen.

In yet still another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, where R4 is halogen, such as chloro.

In yet still another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is chloro, and R3, R5, R6, and R7 are H.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, or wherein at least one of R3, R4, or R5 is chloro, and R6 and R7 are H.

In another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, CF3, or CN;

R4 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, CN, phenyloxy, —SO2—(C1-C4 alkyl), —NR10R11, C1-C4 alkanoyl, and

R5 is hydrogen, C1-C4 alkyl, —SO2NR10R11 or halogen.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or Hid, wherein R4 is halogen (in one aspect, F or Cl), C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, or CN.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3, R4, R5, R6, and R7 are independently hydrogen, F, CF3, CHF2 or methyl.

In another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4, R5, R6, and R7 are hydrogen.

In yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is halogen, such as chloro.

In another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, CF3, or CN;

R4 is oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R5 is hydrogen, C1-C4 alkyl, —SO2 NR10R11, or halogen.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 is halogen (in one aspect, F or Cl), CH3, OCH3, CF3, or OCF3.

In another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3 is hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, CF3, or CN;

R4 is hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, C1-C2 haloalkoxy, CN, —NR10R11, C2-C3 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, or thienyl;

R5 is hydrogen, CH3, or F; and

R6 and R7 are independently hydrogen or halogen.

In still yet another aspect, the invention provides compounds of Formula IIId, wherein R4 is CF3, or OCF3.

In yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 and R5, or R5 and R6 and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 or 2 groups that are independently halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN or NO2.

In still yet another aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R4 and R5, or R5 and R6 and the carbons to which they are attached form a pyridyl, pyrrolyl, thienyl, furanyl, pyrrolidinyl, piperidinyl ring, each of which is optionally substituted with 1, 2, or 3 groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms (such as F).

In one aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R6 and R7 are independently hydrogen or methyl.

In one aspect, the invention provides compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R3 and R5 are independently hydrogen, halo, or methyl.

In another aspect, the invention provides compounds of Formula IV, i.e., compounds of Formula II, wherein the A-ring is C3-C8 cycloalkyl, which is optionally substituted at a substitutable position with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, C0-C3alkylCO2R′, heteroaryl, heterocycloalkyl, phenyl, aralkyl, or —SO2NR10R11.

In yet another aspect, the invention provides compounds of Formula IV wherein

0 or 1 of the carbons in the [3.2.1] ring system is optionally replaced with an —O—, —S(O)x, or —NR15— group; where R15 is hydrogen, C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, or phenyl, where the phenyl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2, where x is 0, 1 or 2 and

where the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In yet another aspect, the invention provides compounds of Formula IVa, i.e. compounds of Formula IV having the formula:

wherein no carbons in the ring system are replaced with an —O—, —S(O)x—, or —NR15— group, and

where the [3.2.1] ring is optionally substituted 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In still yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with oxo, —O(C1-C2alkyl)O—, or —S(C1-C2 alkyl)S—.

In another aspect the invention provides compounds of Formula IV or IVa wherein the [3.2.1] ring is substituted with —O—SO2—(C1-C6 alkyl).

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with ═N—NR12, or ═N—O—R13; where

R12 is hydrogen, C1-C6 alkyl or —SO2— phenyl, where the phenyl is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2; and

R13 is hydrogen or C1-C6 optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In yet still another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with ═N—NR12, where R12 is hydrogen, C1-C6 alkyl or —SO2-phenyl, where the phenyl is optionally substituted with 1 to 4 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with ═N—O—R13; where R13 is hydrogen.

In still yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is ═N—O—R13; where R13 is C1-C6 optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2.

In another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is not substituted.

In yet another aspect, the invention provides compounds of Formula IV or IVa, wherein the [3.2.1] ring is substituted with aryl or heteroaryl, such as phenyl or pyridyl, both aryl and heteroaryl are optionally substituted with halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is C2-C6 alkenyl.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is C1-C6 alkyl.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is phenyl.

In still another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is oxo.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is arylalkyl; more preferably, aryl(C1-C4)alkyl; still more preferably, phenyl(C1-C4)alkyl; yet still more preferably, benzyl.

In yet another aspect, the invention provides compounds of Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or 2 groups, at least one of which is hydroxyl or C1-C6 alkoxy.

In yet another aspect, the invention provides compounds of Formula IVa1, i.e. compounds of Formula IV wherein,

one carbon of the [3.2.1] ring system is replaced with an —O—, —S(O)x—, or —NR15— group, where x is 0, 1 or 2;

the [3.2.1] ring is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —NR′COR″, CN, ═N—NR12, or ═N—O—R13; and

R15 is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO2R′, —C(O)R′, —C(O)OR′, or C1-C6 alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl (such as CF3), C1-C4 haloalkoxy (such as OCF3), CN, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl) (C1-C6 alkyl), or NO2.

In yet another aspect, the invention provides compounds of Formula IVb, i.e., compounds of Formula IV having the following formula:

In another aspect, the invention provides compounds of Formula IVb, wherein R15 is hydrogen.

In yet another aspect, the invention provides compounds of Formula IVb, wherein R15 is C1-C6 alkyl.

In yet another aspect, the invention provides compounds of Formula IVb, wherein R15 is C1-C6 alkyl substituted with phenyl, hydroxyl, or halogen, where the phenyl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl (such as CF3), C1-C4 haloalkoxy (such as OCF3), CN or NO2.

In yet another aspect, the invention provides compounds of Formula IVb, wherein R15 is phenyl optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl (such as CF3), C1-C4 haloalkoxy (such as OCF3), CN or NO2.

In still another aspect, the invention provides compounds of Formula IVb, wherein R15 is C1-C6 alkyl substituted with hydroxyl or halogen.

In yet another aspect, the invention provides compounds of Formula IVc, i.e., compounds of Formula IV having the following formula:

where the [3.2.1] ring is optionally substituted 1, 2, or 3 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In yet another aspect, the invention provides compounds of Formula IVd, i.e., compounds of Formula IV having the following formula:

where the [3.2.1] ring is optionally substituted 1, 2, or 3 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —OS(O)2R′, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In yet another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cyclopropyl.

In still yet another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cyclobutyl.

In yet still another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cyclopentyl.

In another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cyclohexyl.

In yet still another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cycloheptyl.

In still yet another aspect, the invention provides compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the C3-C8 cycloalkyl group is cyclooctyl.

In another aspect, the invention provides compounds of Formula V, i.e. compounds of Formula II, wherein the A-ring is heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6-alkanoyl, C0-C3alkylCO2R′, heteroaryl, heterocycloalkyl, aryl, aralkyl, or —SO2NR10R11.

In still another aspect, the invention provides compounds of Formula Va, i.e. compounds of Formula V having the following formula:

wherein:

the A-ring is heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy, —S(O)0-2—(C1-C6 alkyl), —NR10R11, C1-C6 alkanoyl, C0-C3alkylCO2R′, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl C1-C4 alkyl; or —SO2NR10R11;

zero of the carbons in the [3.2.1] ring system is replaced with an —O—, —S(O)x—, or —NR15— group; and

the [3.2.1] ring is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C1-C6 alkyl, —O(C1-C2 alkyl)O—, —S(C1-C2 alkyl)S—, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 alkynyl, hydroxy, hydroxyalkyl, C1-C6 alkoxy, haloalkoxy, —C(O)OR13, —(C1-C4 alkyl)-C(O)OR13, —CONR10R11, —OC(O)NR10R11, —NR′C(O)OR″, —NR′S(O)2R″, —NR′COR″, CN, ═N—NR12, or ═N—O—R13.

In still another aspect, the invention provides compounds of Formula V or Va, wherein the [3.2.1] ring is substituted with oxo, —O(C1-C2 alkyl)O—, or —S(C1-C2 alkyl)S—.

In another aspect the invention provides compounds of Formula V or Va wherein the [3.2.1] ring is substituted with —O—SO2—(C1-C6 alkyl).

In still another aspect, the invention provides compounds of Formula V or Va, wherein the [3.2.1] ring is substituted with ═N—NR12, or ═N—O—R13; where

R12 is hydrogen, C1-C6 alkyl or —SO2— phenyl, where the phenyl is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, CF3, OCF3, CN or NO2; and

R13 is hydrogen or C1-C6 optionally substituted with phenyl, hydroxyl, or halogen, where the phenyl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, O1—C4 haloalkyl, C1-C4 haloalkoxy, CN or NO2.